@article{dd7e869217414d63a5a0a33f78789f8d,
title = "Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine crosstalk between PSCs and PDAC is orchestrated by the utilization of specifi c transporters. PSCs utilize SLC1A4 and other transporters to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal-cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer. SIGnIFICAnCE: This work identifi es critical neutral amino acid transporters involved in channeling alanine between pancreatic stellate and PDAC cells. Targeting PDAC-specifi c alanine uptake results in a metabolic crisis impairing metabolism, proliferation, and tumor growth. PDAC cells specifi cally activate and require SLC38A2 to fuel their alanine demands that may be exploited therapeutically.",
author = "Parker, {Seth J.} and Amendola, {Caroline R.} and Hollinshead, {Kate E.R.} and Qijia Yu and Keisuke Yamamoto and Joel Encarnaci{\'o}n-Rosado and Rose, {Rebecca E.} and LaRue, {Madeleine M.} and Sohn, {Albert S.W.} and Biancur, {Doug E.} and Paulo, {Joao A.} and Gygi, {Steven P.} and Jones, {Drew R.} and Huamin Wang and Philips, {Mark R.} and Dafna Bar-Sagi and Mancias, {Joseph D.} and Kimmelman, {Alec C.}",
note = "Funding Information: The authors would like to thank Haoqiang Ying for providing the HY19636 and HY15549 cell lines. The authors would like to thank all members of the Kimmelman and Pacold labs for critical discussions and guidance. Specifically, the authors would like to thank Michael Pacold for feedback on the manuscript. The authors would like to thank Caitlyn Bowman for helpful discussions and suggestions surrounding mitochondrial pyruvate transport and alanine. The authors would like to acknowledge the Experimental Pathology Research Laboratory for their expertise and assistance with processing, embedding, sectioning tissue sections, and imaging of slides. This work was supported by NCI grants R01CA157490, R01CA188048, P01CA117969, and R35CA232124; ACS Research Scholar grant RSG-13-298-01-TBG; NIH grant R01GM095567; P30CA016087; a Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Translational Cancer Research grant (SU2C-AACR-DT26-17; to A.C. Kimmelman); R01GM132129, to J.A. Paulo; and R01CA196941, to H. Wang. D.E. Biancur was supported by an NCI Predoctoral to Postdoctoral Fellow Transition Award F99CA245822. K. Yamamoto was supported by a Uehara Memorial Foundation Research Fellowship. S.J. Parker was supported by American Cancer Society grant 132942-PF-18-215-01-TBG. Stand Up To Cancer (SU2C) is a division of the Entertainment Industry Foundation. The above-mentioned research grant is administered by the American Association for Cancer Research, the Scientific Partner of SU2C. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
doi = "10.1158/2159-8290.CD-19-0959",
language = "English (US)",
volume = "10",
pages = "1018--1037",
journal = "Cancer discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "7",
}